Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction

Biochem Biophys Res Commun. 2016 Jun 17;475(1):1-7. doi: 10.1016/j.bbrc.2016.04.123. Epub 2016 Apr 24.

Abstract

Type 5 adenylyl cyclase (AC5) plays an important role in the development of chronic catecholamine stress-induced heart failure and arrhythmia in mice. Epac (exchange protein activated by cAMP), which is directly activated by cAMP independent of protein kinase A, has been recently identified as a novel mediator of cAMP signaling in the heart. However, the role of Epac in AC5-mediated cardiac dysfunction and arrhythmias remains poorly understood. We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG-Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion. Decreased cardiac function as well as increased susceptibility to pacing-induced atrial fibrillation (AF) in response to ISO were significantly attenuated in AC5TG-Epac1KO mice, compared to AC5TG mice. Increased cardiac apoptosis and cardiac fibrosis were also concomitantly attenuated in AC5TG-Epac1KO mice compared to AC5TG mice. These findings indicate that Epac1 plays an important role in AC5-mediated cardiac dysfunction and AF susceptibility.

Keywords: Adenylyl cyclase; Arrhythmia; Catecholamine; Epac; Heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • Apoptosis
  • Atrial Fibrillation / etiology
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology*
  • Catecholamines / metabolism*
  • Fibrosis
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Stress, Physiological

Substances

  • Catecholamines
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Adenylyl Cyclases
  • adenylyl cyclase type V